Appropriate use of colistin in neonates, infants and children: Interim guidance

No abstract available. 


Introduction
This document provides interim recommendations for appropriate colistin use (polymyxin E) to treat bacterial infections in neonates, infants, and children.
Colistin, a polymyxin antibiotic, was first used clinically in the 1950s.Colistin is commercially available in two forms -colistin sulphate (oral or topical powder) and colistimethate sodium (CMS) (parenteral formulation). 1Colistin acts upon the Gram-negative bacterial outer cell membrane by disrupting magnesium and calcium ions.The disturbance increases cell permeability, resulting in leakage of cell contents, and ultimately cell death. 1,2Colistin resistance can be intrinsic or acquired.Gram-negative bacteria with intrinsic resistance to colistin include Serratia marcescens, Proteus spp., Morganella spp., Providencia stuartii, and Burkholderia cepacia complex. 3Acquired resistance can be chromosomal or plasmid-mediated.
In South Africa, colistin is commonly available as vials containing 1-million international unit (IU) of CMS powdered for reconstitution.Colistimethate sodium is a prodrug, which is converted in the plasma to active colistin.Each 1-m-unit of CMS vial contains approximately 34 mg colistin base activity (CBA), or 80 mg CMS.Package insert should always be consulted for quantitative vial composition.
Antimicrobial resistance (AMR) is a global public health and One-Health problem, and is considered to the next great global challenge. 4By 2050, an estimated 10m deaths per year will be attributable to AMR. 5 More recently, infections with AMR pathogens caused around 1.2m deaths globally and was associated with 4.95m deaths globally in 2019. 6e most concerning pathogens are those listed by the World Health Organization (WHO) as priority pathogens.Among these, those categorised as critical pathogens are all Gram-negative bacteria.The latter include extended spectrum β-lactamase producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. 7Research and development (R&D) of new antimicrobial agents for these pathogens is critical.
Although all age groups are at risk of AMR infections, children under the age of 5 are particularly vulnerable, with 1 in 5 deaths attributable to AMR occurring in this age group.Children living in sub-Saharan Africa are particularly affected by AMR pathogens compounded by a lack of access to effective antimicrobials. 6e emergence of extensively drug resistant (XDR) pathogens (an isolate that is non-susceptible to at least one agent in all but two or fewer antimicrobial categories) has resulted in renewed use http://www.sajid.co.zaOpen Access of colistin. 1,8Several guidelines address optimal use of colistin in adults, but these do not adequately address using colistin in neonates and children. 2,9This document aims to provide practical guidance to clinicians for appropriate use of colistin in neonates, infants, and children.Table 1 presents a summary of the recommendations.

Methods
A panel of clinical microbiologists, paediatric infectious diseases specialists, neonatologists and clinical pharmacologists was convened, representing the National Health Laboratory Service (NHLS), the South African Paediatric Association (SAPA), the United South African Neonatal Association (USANA), the Federation of Infectious Diseases Societies of Southern Africa (FIDSSA), and the South African Society of Paediatric Infectious Diseases (SASPID) to develop consensus guidance and interim recommendations for colistin use in neonates, infants, and children.
Through teleconference meetings, important concepts related to colistin use in neonates, infants and children were discussed.These topics were then assigned to panel members.Follow up meetings were held where existing evidence of colistin use in neonates, infants, and children was presented.The literature review consisted of studies published before end December http://www.sajid.co.zaOpen Access Thereafter, the panel generated and agreed upon a list of questions, which the guidance document aimed to answer.Panel members were divided into groups to address each clinical question.Each panel member reviewed and evaluated the literature and proposed recommendations with a brief summary of evidence.
The draft recommendations were then reviewed by the full panel.Divergences among panellists' views were resolved through internal discussion.The finalised draft was reviewed by the USANA, the SAPA and the FIDSSA for endorsement.
Because of the scarcity of published literature in this patient population, grading of evidence, although difficult, was included.
Strength of recommendations: • Strong: high level of confidence that there are strong benefits from this recommendation.• Moderate: relative confidence for this recommendation.
• Weak: little confidence in the beneficial effects of this recommendation.
Quality of evidence: • High: includes randomised controlled trials, systematic reviews, and meta-analyses.• Moderate: non-randomised trials, cohort studies, casecontrol studies or diagnostic accuracy studies.• Low: evidence based on clinical experience or expert opinion.

Definitions
Definitions of severe sepsis and septic shock are included here, but the reader is recommended to refer to the Surviving Sepsis Guidelines for detailed definitions. 10vasive infections: although this is not a comprehensive list, examples include bacteraemia, meningitis, necrotising enterocolitis (NEC)/intra-abdominal infection, bacteraemic pneumonia, bone and joint infections.
Non-severe infections: include urinary tract infection (UTI), superficial skin or soft tissue infection.
Severe sepsis: • ≥ 2 age-based systemic inflammatory response syndrome (SIRS) criteria • Confirmed or suspected invasive infection • Cardiovascular dysfunction, acute respiratory distress syndrome (ARDS), or ≥ 2 non-cardiovascular organ system dysfunctions. 10ptic shock: the subset of severe sepsis patients with cardiovascular dysfunction, which includes hypotension, treatment with a vasoactive medication, or impaired perfusion. 10itically ill: a patient with a severe airway, breathing or circulatory problem, or acute deterioration of conscious state.

See the following recommendations regarding empiric use of colistin
What is the recommended method for testing and reporting colistin minimum inhibitory concentration results?

Recommendation
Broth microdilution is the only reliable method for determining colistin MICs according to European Committee on Antimicrobial Susceptibility Testing (EUCAST). 12,13

A summary of evidence
The CLSI and EUCAST are the two organisations that provide susceptibility breakpoints for colistin.
Challenges in the setting of breakpoints for colistin include: (1) difficulties in providing a reproducible MIC below 2 mg/L because of challenges in the test system; (2) in vivo levels of 2 mg/L required for bactericidal action, which is very difficult to obtain in patients with normal renal function; (3) MIC distribution data indicates that 2 mg/L is the most reliable cut-off point to separate wild type isolates from those with resistance mechanisms for the Enterobacterales and A. baumannii, but higher (4 µg/L) for P. aeruginosa. 14e current (2022) CLSI guidelines have set colistin breakpoints for Enterobacterales, P. aeruginosa, and Acinetobacter spp at ≤ 2 mg/L (intermediately susceptible) and ≥ 4 mg/L (resistant), with no susceptible category (Table 2). 12The CLSI definition of the intermediate category implies uncertainty related to susceptibility testing, clinical outcome, dosing, and administration.
In contrast, EUCAST has maintained the susceptibility category, for A. baumannii and the Enterobacterales at ≤ 2 mg/L, and resistant if > 2 mg /L.Pseudomonas aeruginosa has slightly higher breakpoints (susceptible if ≤ 4 mg/L and resistant if > 4 mg/L) (Table 2). 13ropean Committee on Antimicrobial Susceptibility Testing introduced brackets for the colistin breakpoint.This is to warn against using colistin without additional therapeutic measures.Breakpoints in brackets represent the epidemiological cut-off value (ECOFF), which distinguishes isolates with and without acquired resistance mechanisms. 13at is the recommended colistin PK/PD target for efficacy?

A summary of evidence
Colistin loading doses in adult patients are recommended and well established. 2A colistin loading dose prevents exposure to sub-therapeutic concentrations for a prolonged period during initial treatment, as colistin concentrations rise slowly after administration. 2e Food and Drug Administration (FDA) and the European Medicines Agency (EMA) currently suggests no paediatric loading dose with a maintenance colistin dose of 2.5 mg to 5 mg CBA/kg per day. 18,19The reason for no loading dose is mainly because of a lack of robust PK and safety data in the paediatric population.Recent PK studies in children and neonates have however shown that the FDA-and EMA-recommended colistin doses are insufficient for optimal efficacy according to recommended Pharmacokinetics (PK), pharmacodynamics (PD) parameters. 15,20,21To our knowledge, there is only report on the pharmacokinetics of colistin in neonates. 20This was a prospective, open label study, performed in neonates (5-15 days of life) receiving colistin within a neonatal intensive care unit. 20Further elaboration on loading dose is available in the supplementary document.In addition, paediatric colistin studies reported reversible nephrotoxicity in 3% -10% of patients, 17 but the impact of immature neonatal metabolic and renal function on the metabolism and elimination of colistin has not been assessed.
Based on evidence that the standard 5 mg CBA/kg per day colistin doses without loading doses produce suboptimal exposures, 22,23 and given the emerging paediatric and neonatal PK data of colistin showing benefits of a colistin loading dose and likely subtherapeutic concentrations with the suggested maintenance dose, we recommend a colistin loading dose of 4 mg -5 mg CBA/kg body weight, followed by 2.5 mg CBA/kg twice daily maintenance dose in neonates, children, and infants.This should be performed with close monitoring of renal function (see 'How should adverse effects be monitored and how often').
It is important to observe that therapeutic drug monitoring to guide colistin dosing is not available in South African at the time of publication.

A summary of evidence
Overall, fewer paediatric patients experience colistin-associated acute kidney injury than adults. 22Colistin renal dose adjustments in adults are well established but are lacking for the paediatric population. 2,18Most paediatric studies evaluating the pharmacokinetics of colistin exclude patients with renal impairment. 20,23,24A recent population pharmacokinetic study of colistin explored covariates influencing target attainment in a population with a median age of 2.6 years (interquartile range [IQR] 0.8-6.8years).Creatinine was a significant covariate and colistin dosing adjustments are proposed in impaired renal function.However, the proposed dosage changes have not been validated.
The pharmacokinetics of colistin in paediatric patients receiving renal replacement therapy (RRT) have not been adequately evaluated.No recommendations can be made concerning colistin dosing in patients receiving RRT.In adult patients, dose adjustments are recommended depending on the type of RRT received. 2In the absence of data, colistin dosing regimens during RRT should be selected through a multidisciplinary team approach, including neonatologists, nephrologists, microbiologists, clinical pharmacologists, infectious disease specialists, and chemical pathologists.

How should colistin therapy be administered? Recommendation
Colistin may be administered as a slow bolus injection or as a slow infusion over 30 min.

A summary of evidence
The contents of the vial can be reconstituted and administered as a slow bolus injection over 3 to 5 min or as an infusion over 30 min. 18,19The volume chosen for infusion should be determined by patient's fluid requirements.Table 3 is a CMS conversion table. 18Refer to Online Appendix 1 for a practical, stepwise approach to administering CMS.

When treating an infection with colistin, is monotherapy or combination therapy recommended? Recommendation for carbapenemase producing enterobacterales (CPE)/carbapenem resistant enterobacterales
Combination therapy with a second active antibiotic is recommended in those patients with severe sepsis or septic shock at presentation, bloodstream infection (BSI) with a non-urinary/non-biliary source of infection or severe underlying disease.Factors for consideration when selecting the second active antibiotic (meropenem, tigecycline, aminoglycoside, other) include the site(s) of infection, the antibiotic MICs and patient renal function.High dose prolonged infusion meropenem can be used when the MIC is ≤ 8 mg/L.
For non-severe infections (e.g.uncomplicated UTI) colistin monotherapy can be considered in the absence of other appropriate treatment options.

A summary of evidence
Several factors support combination therapy: in vitro data showing synergy of antibiotic combinations, lower efficacy of colistin monotherapy compared with β-lactam monotherapy, the potential to reduce mortality in severely ill patients, lower risk of resistance development (e.g. against colistin), and shorter treatment duration.However, several facts argue against combination therapy: the possible rise in resistance rates because of an overall increase in selection pressure following greater release of antibiotics into the environment, higher rates of adverse effects (such as nephro-and ototoxicity because of colistin or aminoglycosides), increased Clostridioides difficile-associated infections, fungal infections, higher costs, and possible antagonism. 25though data supporting combination therapy is sparse, and largely for adults with Klebsiella pneumoniae Carbapenemase (KPC) BSIs, recent meta-analyses concluded that combination therapy reduces mortality and improves clinical outcomes in patients with BSIs because of CPE. 25,26e newer β-lactam-β-lactamase inhibitor combinations are not readily accessible in many countries, resulting in limited treatment options being available for CRE infections.Available treatments include colistin, the aminoglycosides, tigecycline and PK/PD-optimised doses of meropenem.The selection of specific antibiotics must be based on the likelihood of achieving therapeutic drug levels at the site of infection (site of infection, antibiotic MIC and PK/PD parameters) without irreversible or severe adverse effects related to the drug.
Data from observational studies on combination therapy are inconsistent. 2 The second agents used in these patients varied and included colistin, tigecycline and aminoglycosides.In contrast, the AIDA and OVERCOME randomised controlled trials (RCTs) did not find a significant survival benefit of colistinmeropenem combination therapy over colistin monotherapy in patients with severe CPE infections. 29,30her studies show a benefit of combination therapy only with severe sepsis or septic shock at presentation, BSI with non-urinary/non-biliary source of infection, or severe underlying disease. 31,32A systematic review and metaanalysis comparing monotherapy to combination therapy for MDR Gram-negative infections demonstrated reduced mortality in BSIs and in infections caused by CPEs when combination therapy comprising two active antibiotics was used. 25There was no reduction in mortality when combination therapy included only one active antibiotic.Clinical cure rates with mono-and combination therapy were the same.Overall, the quality of studies included in this analysis was low.The improved outcomes observed when colistin is combined with other antibiotics may be because of suboptimal pharmacokinetic properties of colistin.
Based on the available evidence, combination therapy is recommended in patients with CPE infections who have severe sepsis or septic shock at presentation, BSIs with a nonurinary/non-biliary source of infection or severe underlying disease.

Recommendation for extensively drug resistant Acinetobacter baumannii
Combination therapy with a second active antibiotic is recommended for severe sepsis/septic shock.Factors to be considered when selecting the second active antibiotic (meropenem, tigecycline, aminoglycoside etc.) include the site and source of infection, the antibiotic MICs, and patient renal function.

A summary of evidence
The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of ABR and the risk of severe side effects. 25e AIDA RCT compared colistin monotherapy to colistinmeropenem combination therapy in 406 patients, for severe infections (largely pneumonia and bacteraemia caused by A. baumannii), they however, did not find a difference in clinical outcomes. 29A planned sub-analysis of the subset of infections caused by organisms with meropenem MICs ≤ 16 mg/L was not possible because of low numbers.The OVERCOME RCT, which also compared colistin to colistin-meropenem combination therapy for carbapenem-resistant Gram negative pneumonia and BSI found no survival benefit with combination therapy. 30The XDR A. baumannii isolates prevalent currently have high carbapenem MICs (> 8 mg/L) (unpublished data) and the findings of the cited studies do not support the routine use of colistin-carbapenem combination therapy.
Similarly, despite in vitro studies demonstrating synergy when colistin is combined with rifampicin for A. baumannii, current clinical data do not support the use of colistinrifampicin combination therapy. 33,34e XDR A. baumannii isolates prevalent in the South African public health sector currently have high carbapenem MICs (> 8 mg/L).The evidence supporting combination therapy for A. baumannii is of low quality.However, the pharmacokinetic properties of colistin result in suboptimal drug levels at some infection sites when administered intravenously.This, together with its narrow therapeutic window, can result in limited clinical efficacy for many infections. 2 In addition, delays in appropriate therapy (because of the MDR phenotype) may result in high bacterial burdens.Hence, combination therapy with a second active antibiotic is recommended in those patients with severe sepsis/septic shock.If a second active agent is not available, colistin monotherapy is recommended.For patients with non-severe infections (e.g.uncomplicated UTI) colistin monotherapy can be considered in the absence of other appropriate treatment options.

Recommendation for extensively drug resistant Pseudomonas aeruginosa
Combination therapy with a second active antibiotic is recommended for severe sepsis or septic shock at presentation, BSI with a non-urinary/non-biliary source of infection or severe underlying disease.
For patients with non-severe infections (e.g.uncomplicated UTI), colistin monotherapy can be considered in the absence of other appropriate treatment options.

A summary of evidence
There is little data available limiting a robust recommendation.
In the small number of carbapenem-resistant P. aeruginosa cases included in the AIDA and OVERCOME RCTs, no survival benefit was demonstrated for colistin-carbapenem combination therapy over colistin monotherapy. 29,30Available data are mainly small retrospective studies that used a variety of active and non-active second antibiotic agents, and it is not possible to make conclusions about the value of colistincombination therapy.
It is suggested that combination therapy is used in those patients with severe sepsis/septic shock and colistin monotherapy is used for non-severe infections.

When is empiric treatment with colistin indicated? Recommendation
In authors' view, empiric colistin therapy can be considered in critically ill patients in centres where invasive infections caused by carbapenem-resistant Gram-negative pathogens are prevalent.However, empiric colistin should be stopped as soon as possible e.g.alternative antibiotic active against isolate, clinical improvement, exclusion of invasive infection, non-infectious cause for illness identified.

For most patients, empiric colistin use is strongly discouraged. It is recommended that empiric use of colistin be approved through the hospital AMS committee on a case-by-case basis.
When empiric colistin treatment is being considered, it should only be initiated following consultation with a clinical microbiologist, neonatologist or infectious diseases specialist as there are frequently better alternatives available.Strict guidelines must be in place to

guide the empiric use of colistin to prevent overuse of this last resort antibiotic and risk of colistin resistance (see AMS recommendations).
It is controversial as to whether colistin should ever be prescribed empirically that is without confirmed or presumptive infection with a carbapenem-resistant Gramnegative pathogen.
The possible harms related to delayed initiation of potentially life-saving treatment must be weighed up against the benefits of preserving activity for this 'last-line' agent against highlyresistant bacteria.Table 4 outlines a step-by-step guide for prescribing colistin empirically.

A summary of evidence
Infections with XDR Gram-negative organisms are associated with increased mortality.One possible explanation for the increased mortality seen is the likely delay in starting treatment with an appropriate empiric antimicrobial, as none of these organisms would be susceptible to the standard empiric treatment regimens used.Inappropriate empiric antibiotic therapy and delays in starting appropriate antimicrobial therapy are associated with increased mortality. 35,36,37A recent study looking at starting empiric colistin/imipenem in patients with severe sepsis showed a significant reduction in vasopressor requirement and faster improvement in inflammatory markers when treatment was appropriate. 38The choice of empiric antimicrobial therapy should be based on the local epidemiology of isolated pathogens as well as culture-site specific local antibiograms (e.g., blood culture specific antibiograms).Empiric use of colistin in units with a high burden of XDR Gram-negative bacteria (> 15% XDR) may be considered, but could lead to the overuse of this last resort antibiotic and increase the risk of colistin resistance.Therefore, strict guidelines must be in place to guide the empiric use of colistin for suspected invasive infection with XDR Gram-negative bacteria.Access to facility level data in the South African public sector is available on the NICD dashboard. 39

Should inhaled colistin be used to treat hospitalacquired pneumonia/ventilator-associated pneumonia? Recommendation
Inhaled colistin in ventilator-associated pneumonia (VAP) because of colistin-only susceptible Gram-negative bacteria in critically ill children is not routinely recommended.
However, inhaled colistin, in addition to systemic colistin, may be considered in VAP because of colistin-only susceptible Gramnegative bacteria for treatment failure by systemic colistin alone and with the availability of small particle nebulisers.
Although inhaled colistin may be a beneficial adjunct to IV colistin by leading to shorter time to bacterial eradication, significant differences in the clinical and microbiological outcomes of children with VAP have not been demonstrated.
http://www.sajid.co.zaOpen Access When considering adding inhaled colistin to systemic colistin, prior consultation with a paediatric infectious disease specialist/ microbiologist is recommended.

Practical considerations
• Ensure optimal dosing of systemic colistin before adding inhaled colistin.• The ideal nebuliser should be able to deliver colistin particles of < 3 µm diameter.• Administer immediately after dissolving in 4 mL sterile isotonic saline solution over 15 min at a dose of 4 mg CBA/kg 12 hourly (120 000 IU/kg 12 hourly).• Monitor for respiratory side effects, for example, bronchospasm.

A summary of evidence
The hydrophilic structure of colistin limits its penetration into lung parenchyma. 41Nebulised colistin potentially achieves higher concentrations in the airways with less systemic toxicity, compared with intravenous (IV) colistin. 42,43o reach the lung parenchyma, the particle size, expressed as mass median aerodynamic diameter (MMAD), should be about 3 µm. 44Most nebulisers are designed to effectively deliver drug to the airways, not the lung parenchyma, and create aerosols of 5 µm MMAD. 44Nebulisers able to provide sufficiently small particles (< 3 µm) to reach the lung parenchyma include jet, ultrasonic, and vibrating-mesh nebulisers. 45In addition, the absorption rate will depend on many factors including the location of deposition (central versus peripheral) as well as the volume and mechanical properties of airway secretions. 43though inhaled colistin is widely used for cystic fibrosis (CF), the pharmacodynamics might be different in a patient without chronic lung disease. 46,47The bacteria in patients with CF are mainly found in the mucus rather than on the epithelial surface. 43e evidence for inhaled colistin in adults with VAP because of multidrug resistant (MDR) Gram-negative organisms is of low quality. 48Expert opinion from professional societies, such as the Infectious Disease Society of America (IDSA) and the European Society for Clinical Microbiology (ESCMID) are conflicting. 49The evidence for inhaled colistin in the paediatric population is limited to small retrospective studies, with no respiratory complications reported: most infants received inhaled colistin in addition to active systemic antibiotics. 50,51Monotherapy with inhaled colistin (without systemically administered antibiotics) was successful in 17 neonates. 52,53A matched case control study found that infants treated with nebulised colistin plus systemic colistin, had better outcomes than infants treated with systemic colistin alone. 54The addition of inhaled colistin to IV colistin led to a shorter time to bacterial eradication in critically ill children with VAP because of colistin-only susceptible GNB.However, it did not lead to a significant difference in the clinical and microbiological outcomes of VAP. 55

TABLE 4:
Step-by-step guide for empiric colistin use.

Risk assessment and management Guidance Additional information
Step A PK/PD study suggested that a dose of 4 mg CBA/kg (120 000 IU/kg) attained high colistin levels in tracheal aspirate from neonates for 12 h. 56verse effects associated with inhaled colistin are bronchospasm and nephrotoxicity.High concentrations may cause damage to the airways.Nebulised steroids and β-2-agonists can be used to prevent and treat bronchospasm. 44ould intraventricular/intrathecal colistin be used to treat meningitis?

Recommendation
The use of intraventricular/intrathecal colistin in combination with IV colistin can be considered in patients with suitable indwelling devices and clinical/microbiological indications for colistin therapy (See above recommendations for indications).In addition, for patients without a suitable indwelling device but persistent CNS infection despite maximum recommended IV colistin dosing, neurosurgery and microbiology/infectious diseases consultation is recommended prior to initiating intraventricular/intrathecal colistin.Proposed dosing of intrathecal/intraventricular colistin is detailed in Table 5.

Summary of evidence
Colistin does not cross the blood-CSF barrier well. 57ntrathecal (through the lumbar thecal sac) or intraventricular (lateral ventricle) dosing of colistin bypasses this barrier and can achieves much higher CSF colistin levels than with IV dosing.
Intrathecal and intraventricular colistin administration has not been well studied. 58.59,60,61,62We therefore, recommend consideration in patients with suitable indwelling devices, such as lumbar or external ventricular catheters/drains.For patients without a suitable indwelling device but persistent CNS infection despite maximum recommended IV colistin dosing, neurosurgery and microbiology/infectious diseases consultation is strongly recommended prior to initiating intraventricular/intrathecal colistin.
Ventricular volume and CSF drainage rates must be considered when selecting a dosing regimen. 63The CSF volume in neonates is small (approximately 5 mL) compared with that in older infants (50 mL) and adults (125 mL -150 mL). 56Doses of 4 mg CBA/day (120 000 IU/day) in adult patients yields CSF through concentrations above 2 mg/L. 23,64he IDSA suggests that for infants, adult intraventricular antimicrobial doses should be reduced by 60% or more.A retrospective review of colistin use for MDR Gram-negative infections in a Pakistan neonatal unit, briefly described the management of 15 cases of meningitis.Seven neonates received intraventricular colistin, five of whom also received IV colistin.The five neonates who received both intraventricular and IV colistin, and one of two who received only intraventricular therapy, survived.None of the eight neonates who received only IV colistin survived.The basis for the dose selection in this unit was not provided. 61dividualised dosing based on predicted ventricular volume and CSF drainage is recommended.Multidisciplinary (neurosurgery, microbiology, infectious diseases, paediatrics and clinical pharmacology) consultation is recommended for dose selection.
If administering intrathecal or intraventricular colistin, a single daily dose is recommended.
How should patients receiving colistin be monitored for adverse events and how frequently?
Recommendation: Nephrotoxicity and electrolytes • Close monitoring of renal function, sodium, potassium and magnesium, with dosage adjustments when necessary (See Online Appendix 1).• Maintain adequate hydration.
• Limit co-administration of other nephrotoxic drugs.
Definitions of acute kidney injury are detailed in Online Appendix 1.The ICU patients requiring organ support require more frequent monitoring but if not requiring organ support, monitoring every 72 h is sufficient.Ideally, monitoring should be clinician directed.Collect a specimen for baseline renal function prior to colistin initiation, but do not delay initiating colistin loading dose while awaiting results.

A summary of evidence
Adverse effects because of colistin have been reported since the early 1960s, mostly from adult studies, with rates as high as 50%. 65Reported adverse effects included nephrotoxicity and less commonly, neurotoxicity.
Data on colistin safety in the neonatal/paediatric population is limited and mostly restricted to retrospective reviews, with recent reported rates of nephrotoxicity ranging from 0% to 24%.These rates have reduced compared with older reports, attributed to improved fluid and electrolyte management in intensive care units, as well as better monitoring of renal function and reduced concomitant use of other nephrotoxic agents.The suggested mechanism of nephrotoxicity is increased membrane permeability, causing tubulopathy, influx of electrolytes and water, leading to cell oedema and lysis. 65Definitions used for nephrotoxicity are not standardised and include an increase in serum creatinine > 50% above baseline, a decrease in urine output below 50% of baseline or < 1 mL/kg/h, or an increase in serum creatinine of > 0.5 mg/dL (44 µmol/L). 66,67,68A case series reported a 19% renal toxicity rate in neonates receiving colistin. 69Another retrospective study in 104 children reported nephrotoxicity in 10.5% of patients receiving colistin. 66These children, however, were also receiving other concomitant nephrotoxic drugs and none on colistin alone developed nephrotoxicity.
Another study reported nephrotoxicity in 2 of the 18 neonates treated with colistin. 67In other retrospective studies in neonates, including preterm neonates, colistin was well tolerated, with no reported cases of renal impairment. 70lectrolyte imbalances, particularly hypomagnesemia, hyponatremia and hypokalemia, are reported in those on colistin.In a retrospective study 12 neonates on IV colistin, 2 had significant hyponatremia and hypokalemia .In this study magnesium replacement was required at least once for all patients. 71Another case-control study that compared 47 neonates who were given colistin with 59 neonates treated with other antimicrobial agents concluded that colistin use was significantly associated with hypokalemia and hypomagnesemia. 72asures used to prevent or limit nephrotoxicity include strict monitoring of renal function with dosage adjustments when necessary, proper hydration and limiting coadministration of other nephrotoxic drugs. 9

Recommendations: Neurotoxicity
• Daily clinical monitoring for neurotoxicity is recommended.
• Inspection for cumulative neurotoxicity by concomitant medication which also cause neurotoxic side effects by reviewing medication chart daily.

A summary of evidence
Neurotoxicity is the second most common adverse effect reported with polymyxins. 73Manifestations of neurotoxicity include dizziness, generalised weakness, muscle weakness, facial and peripheral paraesthesia, partial deafness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, neuromuscular blockade and apnoea. 65Neurotoxicity usually develops in the first 4 days of treatment. 74In a neonatal study, neurotoxicity was not an obvious problem.However, the authors observe that sedation and mechanical ventilation may have affected these findings. 20In a systematic review of polymyxin toxicity, neurotoxicity was reported more frequently in older literature than more recently, but still old, published literature (until 2005). 65Neurotoxicity was reported more frequently after a loading dose was compared in a single study, but this finding was not statistically significant. 65Concomitant administration of colistin with curariform muscle relaxants and other neurotoxic agents must be avoided because these combinations may trigger progression to neuromuscular blockade. 65

A summary of evidence
The optimal duration of antibiotic therapy depends on many factors.The integration of signs of resolution, biomarkers, clinical judgement, and microbiologic eradication might help to define this optimal duration in patients with lifethreatening infections caused by XDR Gram-negative bacteria.It is important to observe that prolonged therapy is not required for infections caused by MDR and XDR pathogens compared with susceptible isolates of the same species. 75ich antimicrobial stewardship tools are recommended while prescribing and administering colistin to patients?[T]he Authority may in writing authorize any person to sell during a specified period to any specified person or institution a specified quantity of any particular medicine, medical device or IVD which is not registered. 85e form comprises six subsections: particulars of the applicant, particulars of the person, institution or company importing the unregistered medicine, particulars of the patient, particulars of the unregistered medicine for which a Section 21 application is being made, informed consent form and a progress report.This should be duly completed by the medical personnel responsible for the patient's management and handed to the relevant pharmacist.This application is then submitted to SAHPRA by the pharmacy departments.(More information concerning the Section 21 application process can be found at https://www.sahpra.org.za/document/2-52section-21-access-to-unregistered-medicines/).and Mycoses (CHARM) at the NICD 'Team Australia' consisting of Jason Roberts, Nicolette Graham, Roger Nation, Amanda Gwee, Cornelia Landersdorfer, Toni Lai for their efforts in trying to help address the question of renal adjustment of colistin dose.

- 3 .
When indicated, start empiric antibiotic treatment after taking cultures, tailoring therapy to the site of infection, risk factors for multidrug-resistant infection and the local microbiology and susceptibility patterns.

- 4 .- 5 .- 6 . 84 - 7 .- 8 .- 9 .- 10 .- 11 .
Prescribe drugs at their optimal dose, mode of administration and for the appropriate length of time, adapted to each clinical situation and patient characteristics.Use antibiotic combinations only in cases where the current evidence suggests some benefit.When possible, avoid antibiotics with a higher likelihood of promoting drug resistance or healthcare-associated infections, or use them only as a last resort.Refer to the WHO AWaRe classification for a comprehensive list of antibiotics classified as 'watch'.Ensure early source control by draining infected foci quickly and removing all potentially or proven infected devices.Always try to de-escalate or streamline antibiotic treatment according to the clinical situation and the microbiological results.Stop antibiotics as soon as a significant bacterial infection is unlikely.Do not work alone.Set up local teams with an infectious diseases specialist, microbiologist, clinical pharmacologists, hospital pharmacist, infection control practitioner or hospital epidemiologist, and comply with hospital antibiotic policies and guidelines.Obtain regular updates (minimum annually) of the unit antibiogram/acquisition of local epidemiologic data to guide treatment decisions. 11

Recommendations What are clinical and microbiological indications for colistin use? Directed/targeted colistin therapy
It is also not active against some Gram-negative bacteria for example S. marcescens, Proteus spp., Morganella spp., P. stuartii and B. cepacia complex.In general, colistin should be initiated based on confirmed or presumptive identification of an invasive XDR Gram-negative infection where no other suitable agent is available.Where possible, treatment with colistin should be in consultation with neonatologist and/or infectious diseases subspecialist.Presumptive identification refers to scenarios where the precise identification and antimicrobial susceptibility profile of an invasive isolate is underway and the patient is in a unit where carbapenem-resistant Gram-negative pathogens are prevalent.Colistin should not be used for non-invasive or superficial infections or to treat colonisation.Clinical signs and symptoms accompanied by identification of an XDR Gramnegative pathogen from a normally sterile site (e.g.blood, cerebrospinal fluid, synovial fluid, serosal fluid) is sufficient justification for colistin treatment.Conversely, identification of such a pathogen from other, not normally sterile sites (e.g.tracheal aspirate, sputum, skin swab, stool) generally should not prompt colistin treatment unless there is compelling clinical, radiological or laboratory evidence suggesting invasive disease -such cases should be discussed with a clinical microbiologist, neonatologist and/or infectious diseases subspecialist before colistin is initiated.

TABLE 2 :
Colistin breakpoints in mg/L as per Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing.
CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing.

TABLE 3 :
Colistimethate sodium conversion table adopted from electronic medicines compendium.

TABLE 5 :
Suggested/proposed colistin intrathecal/intraventricular dose. http://www.sajid.co.zaOpenAccess Where possible, concomitant use should be avoided.Where unavoidable, close daily monitoring by physical examination is necessary and daily review of the prescriptions necessary to determine the need for concomitant use.Of note, however, detecting of neurotoxic symptoms in neonates is challenging.

TABLE 7 :
Examples of colistin bundle elements.

TABLE 6 :
General antimicrobial stewardship principles for colistin use.Obtain high quality appropriate microbiological samples before antibiotic administration and carefully interpret the results.In the absence of clinical signs of infection, colonisation does not require antimicrobial treatment.-2.Avoid the use of antibiotics to 'treat' fever.Investigate the root cause of fever and treat only significant bacterial infections.